This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this project is to understand how immune evasion mechanisms contribute to pathogenesis of Kaposi's sarcoma associated herpesvirus (KSHV) and the development of Kaposi's sarcoma (KS). We focus on the function of two closely related open reading frames, K3 and K5. These proteins, aka MIR1 and MIR2, are viral homologs of the cellular membrane-associated RING-CH (MARCH) protein family comprising transmembrane ubiquitin ligases that recruit cellular ubiquitin-conjugating enzymes for degradation of transmembrane proteins. In the previous funding period we identified novel functions for KSHV-K5 in KSHV-mediated reprogramming of the KS proteome which suggested that these ubiquitin ligases are not only involved in immune evasion, but also in KSHV-mediated tumorigenesis. In these two years, we will address two major questions: 1) What are the consequences of K5 expression for the function of KSHV-infected endothelial cells (ECs) and their interaction with innate immune cells? Using EC-based in vitro models of KS we will examine the modulation of EC/EC and EC/leukocyte adhesion by KSHV. 2) Why and how does KSHV eliminate BST2/Tetherin? Preliminary data show that K5 ubiquitinates and degrades BST2/Tetherin which tethers enveloped viral particles to host cell membranes. We will examine the hypothesis that K5 counteracts the inhibition of KSHV egress by BST2. Upon completion of these studies we will have a better understanding of viral modulation of host processes that are expected to be central to the establishment and maintenance of longterm infection in healthy individuals and KS development in the immunocompromised.[unreadable][unreadable][unreadable][unreadable][unreadable]